This is an application to renew the Northwestern University Morris K. Udall Parkinson's Disease Research Center of Excellence, now in its 15th year. In the last award period, the highly productive research team made significant progress toward understanding the mechanisms underlying Parkinson's disease (PD), resulting in over 40 peer-reviewed publications. Among these discoveries was the recognition that Ca2+ entry through Cav1 channels in dopaminergic neurons in the substantia nigra triggered mitochondrial oxidant stress and increased the vulnerability to genetic mutations and toxins associated with PD. This led to an NINDS-sponsored Phase III clinical trial (slated to be completed in late 2018) to determine whether the Cav1 channel inhibitor isradipine could slow disease progression. In this renewal application, the research team has been re-focused on the implications of this discovery and the broader determinants of vulnerability of dopaminergic neurons, whose loss is responsible for the core motor symptoms of PD. The program continues under the direction of Dr. D. James Surmeier. There are 3 scientific projects, an Administrative Core and a Molecular Core built around this central theme. Project 1, directed by Dr. Surmeier, builds upon the discoveries that motivated the clinical trial to pursue the role of mitochondrial complex I dysfunction in the loss of dopaminergic neurons in PD. This work takes advantage of a new genetic mouse model of PD that captures key features of the human disease. Project 2, directed by Dr. Mark Bevan, uses this same mouse model to determine the role of network dysfunction in driving the loss of dopaminergic neurons in PD. Project 3, directed by Dr. Dimitri Krainc, takes advantage of induced pluripotent stem cell technology to pursue the role of mitochondrial complex I dysfunction, dopamine and familial genetic mutations in determining the vulnerability of human dopaminergic neurons. These projects make use of a shared set of advanced molecular, optogenetic, pharmacogenomic, imaging and electrophysiological approaches to achieve their aims. The Administrative Core, directed by Dr. Surmeier with the assistance of Dr. Tanya Simuni, will be responsible for a wide range of organization activities, including education, career development and outreach. The Molecular Core, directed by Dr. Paul Schumacker, will provide a wide range of services to each of the projects, particularly the development of viral vectors to deliver proteins that will allow investigators to monitor and manipulate key biological processes. The successful attainment of our programmatic goals should bring us closer to meeting the grand challenge facing the PD research community ? to develop a disease-modifying therapy.